VASOCONSTRICTION INCREASES PULMONARY NITRIC-OXIDE SYNTHESIS AND CIRCULATING CYCLIC-GMP

Vascular shear stress increases when blood flow or blood viscosity inc reases or when vessel diameter decreases. In the systemic circulation, shear stress is a potent stimulus for endothelial nitric oxide synthe sis. We studied isolated rat lungs to determine whether increasing she ar stress increases nitric oxide synthesis in the pulmonary circulatio n, Lungs were given the vasoconstrictor, U46619 (a thromboxane analogu e), and perfused at constant how rates or at constant pressure, since constant pressure perfusion minimizes changes in shear stress with vas oconstriction. The subsequent effect of the NOS inhibitor, N-omega-met hyl-L-arginine (LMA), or the soluble guanylyl cyclase inhibitor, 6-ani lino-5,8-quinolinodione (LY83583) was assessed. Changes in pulmonary v ascular resistance (PVR), pulmonary vascular compliance, and perfusate cyclic GMP concentration were measured as indicators of nitric oxide synthesis. The effect of the cyclic GMP-specific (type V) phosphodiest erase inhibitor, zaprinast, on perfusate cyclic GMP concentrations was also examined. An infusion of U46619 consistently increased PVR and d ecreased compliance. LMA and LY83583 also increased PVR in U46619-trea ted lungs perfused at constant flow rates, primarily by increasing pre capillary resistance. LMA had no effect in U46619-treated lungs perfus ed at constant pressure. Perfusate cyclic GMP concentrations increased significantly after U46619 in lungs perfused at constant flow rates, but cyclic GMP levels did not change after U46619 in lungs perfused at constant pressure. Zaprinast also increased perfusate cyclic GMP, dem onstrating that increases in intracellular cyclic GMP are reflected in circulating cyclic GMP concentrations. We conclude that vasoconstrict ion with U46619 increases nitric oxide synthesis in isolated rat lungs . Lungs perfused at constant pressure respond differently to NOS inhib itors compared to those perfused at constant flow, suggesting that she ar stress may increase nitric oxide synthesis in the lung. Perfusate c oncentrations of cyclic GMP reflect activation of soluble guanylyl cyc lase in this model. (C) 1997 Academic Press.